Skin, the largest organ of our body protects us from the attack of foreign pathogens and provides barrier to the permeation of many harmful molecules and maintains the hydration level of tissues. The outer layer of skin, also known as Stratum Corneum (SC) is mainly responsible for these barrier properties.
The delivery of drugs through the skin provides a convenient route of administration because of high surface area of skin and can typically be self-administered. The accurate prediction of dermal uptake of chemicals is therefore relevant to both transdermal drug delivery as well as topical application of cosmetics. In recent past, transdermal delivery of small molecules (hydrophobic/hydrophilic drugs) and macromolecules (proteins, enzymes) has been an attractive as well as a challenging area of research. The transdermal route provides various advantages over conventional oral/intravenous routes. It allows lesser amount of drug to be administered thereby reducing its toxicity. Drugs with poor or less bio-availability can be delivered due to avoidance of the GI tract (a major barrier in oral route). This method provides pain free and easy administration and enhanced patience compliance.
The accurate prediction of dermal uptake of chemicals is relevant to both transdermal drug delivery as well as topical application of cosmetics. Extensive research has been carried out over the many years to predict the skin permeability of various drugs and cosmetic molecules. These efforts include experimental studies, development of theoretical models and empirical methods. The current industry standard, however, both in pharma and in cosmetics, is to conduct detailed in-vitro and in-vivo trials. These obviously incur huge expenses thereby leading to a very few successful candidates that are finally approved by regulatory authority (FDA). The 2-D in vitro cell culture studies do not accurately reflect the complex interactions that occur between the multiple cells present in the 3-D in vivo skin environment. In vivo studies in rodents and other small animals do not translate well to the human situation due to differences in anatomical structures. Though there are some commercially available human skin equivalents like EpiSkin (LOreal, Paris) and EpiDerm™ (MatTek, Massachusetts), these require highly specialized skills and are very expensive.
Further, the European Union (EU) regulation (76/768/EEC, February 2003) prohibits the use of animal or animal-derived substances for the development and testing of cosmetic and pharmaceutical ingredients. The fact that by 2008 only 20 transdermal drug formulations had been approved by FDA substantiates the challenges associated with their development.
Considering the time and costs involved in the development and testing of new drug/cosmetics formulations, it is imperative to supplement/replace some of the elaborate in-vivo/in-vitro tests with in-silico tests. A realistic in-silico model of human skin does not exist. Extensive research has been performed over the last several decades to predict skin permeability of various molecules. These efforts include the development of empirical approaches such as quantitative structure—permeability relationships and porous pathway theories as well as the establishment of rigorous structure-based models. However, a molecular-level understanding of the skin's surface layer—the Stratum Corneum (SC) which shall ultimately lead to the development of rapid in-silico screens to predict drug permeability from knowledge of its molecular structure alone is still not on the horizon. With the recent molecular level decoding of SC's structure, it is now possible to develop an appropriate virtual model to accurately mimic its barrier properties.
Molecular simulations offer a way to yield important physical insight and molecular level resolution with an ability to reproduce molecular and bulk properties. It has been recognized as an efficient and versatile technique for the study of biomolecules like bilayers, micelles and proteins. Various prior arts have focused on factorial design of experiments to screen drugs/cosmetics based on their permeability. Most of the simulation work till now involved only pure ceramide bilayer which is far from the real skin composition. Further, prior simulation work mostly focused on phospholipid cell membranes in liquid crystalline phase which makes sampling easier in molecular dynamic simulations. In addition to that, they only focused on the water permeability. The simulations till now have not been performed at physiological conditions and actual skin compositions.